hhs fda labeling changes

8/14/2019 HHS FDA Labeling Changes

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This document is scheduled to be published in the

Federal Register on 11/13/2013 and available online at

http://federalregister.gov/a/2013-26799, and on FDsys.gov

4160-01-P

DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Parts 314 and 601

[Docket No. FDA-2013-N-0500]

RIN 0910-AG94

Supplemental Applications Proposing Labeling Changes for Approved Drugs and Biological

Products

AGENCY: Food and Drug Administration, HHS.

ACTION: Proposed rule.

SUMMARY: The Food and Drug Administration (FDA or the Agency) is proposing to amend

its regulations to revise and clarify procedures for application holders of an approved drug or

biological product to change the product labeling to reflect certain types of newly acquired

information in advance of FDA's review of the change. The proposed rule would create parity

among application holders with respect to such labeling changes by permitting holders of

abbreviated new drug applications (ANDAs) to distribute revised product labeling that differs in

certain respects, on a temporary basis, from the labeling of its reference listed drug (RLD) upon

submission to FDA of a "changes being effected" (CBE-0) supplement. The proposed rule

describes the process by which information regarding a CBE-0 labeling supplement submitted by

a new drug application (NDA) holder, an ANDA holder, or a biologics license application (BLA)

holder would be made publicly available during FDA's review of the labeling change and

clarifies requirements for all ANDA holders to submit conforming labeling revisions after FDA

has taken an action on the NDA or ANDA holder's CBE-0 labeling supplement. The proposed


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rule also would amend the regulations to allow submission of a CBE-0 labeling supplement for

certain changes to the "Highlights of Prescribing Information" for drug products with labeling in

the "Physician Labeling Rule" (PLR) format.

DATES: Submit either electronic or written comments on the proposed rule by [INSERT DATE

60 DAYS AFTER DATE OF PUBLICATION IN THE FEDERAL REGISTER]. See section

VII for the proposed effective date of a final rule based on this proposed rule. Submit comments

on information collection issues under the Paperwork Reduction Act of 1995 (the PRA) by

[INSERT DATE 30 DAYS AFTER DATE OF PUBLICATION IN THE FEDERAL

REGISTER], (see the "Paperwork Reduction Act of 1995" section of this document).

ADDRESSES: You may submit comments, identified by Docket No. FDA-2013-N-0500 and/or

Regulatory Information Number (RIN) 0910-AG94, by any of the following methods, except

that comments on information collection issues under the PRA must be submitted to the Office

of Information and Regulatory Affairs, Office of Management and Budget (OMB) (see the

"Paperwork Reduction Act of 1995" section of this document).

Electronic Submissions

Submit electronic comments in the following way:

Federal eRulemaking Portal: http://www.regulations.gov. Follow the instructions forsubmitting comments.

Written Submissions

Submit written submissions in the following ways:

Mail/Hand delivery/Courier (for paper or CD-ROM submissions): Division of DocketsManagement (HFA-305), Food and Drug Administration, 5630 Fishers Lane, rm. 1061,

Rockville, MD 20852.


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Instructions: All submissions received must include the Agency name and Docket No. FDA-

2013-N-0500 and RIN 0910-AG94 for this rulemaking. All comments received may be posted

without change to http://www.regulations.gov, including any personal information provided. For

additional information on submitting comments, see the "Comments" heading of the

SUPPLEMENTARY INFORMATION section.

Docket: For access to the docket to read background documents or comments received,

go to http://www.regulations.govand insert the docket number(s), found in brackets in the

heading of this document, into the "Search" box and follow the prompts and/or go to the

Division of Dockets Management, 5630 Fishers Lane, rm. 1061, Rockville, MD 20852.

FOR FURTHER INFORMATION CONTACT: Janice L. Weiner, Center for Drug Evaluation

and Research, Food and Drug Administration, 10903 New Hampshire Ave., Bldg. 51, rm. 6304,

Silver Spring, MD 20993-0002, 301-796-3601.

SUPPLEMENTARY INFORMATION:

Table of Contents

I. Background

A. Drug Labeling

B. Current Requirements Related to Changes to Approved Drug Labeling

C. Specific Labeling Requirements Related to Generic Drugs

D. Recent Court Decisions

II. Description of the Proposed Rule

A. Supplement Submission for Safety-Related Labeling "Changes Being Effected"

(Proposed 314.70(b)(2), (c)(6), and (c)(8) and 601.12(f)(2))


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B. Approval of Supplements to an Approved ANDA for a Labeling Change (Proposed

314.97(b))

C. Exception for ANDA Labeling Differences Resulting From "Changes Being

Effected" Supplement (Proposed 314.150(b)(10)(iii))

III. Legal Authority

IV. Analysis of Impacts

V. Paperwork Reduction Act of 1995

VI. Environmental Impact

VII. Effective Date

VIII. Federalism

IX. Request for Comments

X. References

Executive Summary

Purpose of the Regulatory Action

The Federal Food, Drug, and Cosmetic Act (the FD&C Act) (21 U.S.C. 301 et seq.) and

the Public Health Service Act (the PHS Act) (42 U.S.C. 201 et seq.) provide FDA with authority

over the labeling for drugs and biological products, and authorize the Agency to enact

regulations to facilitate FDA's review and approval of applications regarding the labeling for

those products. FDA is proposing to amend its regulations to revise and clarify procedures for

application holders to change the labeling of an approved drug or biological product to reflect

certain types of newly acquired information in advance of FDA's review of the change through a

CBE-0 supplement. The proposed rule would create parity among application holders with

respect to these safety-related labeling changes by permitting ANDA holders to distribute revised


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generic drug labeling that differs in certain respects, on a temporary basis, from the RLD

labeling upon submission to FDA of a CBE-0 supplement.

Summary of the Major Provisions of the Regulatory Action

The proposed rule would enable ANDA holders to update product labeling promptly to

reflect certain types of newly acquired information related to drug safety, irrespective of whether

the revised labeling differs from that of the RLD. An ANDA holder would be required to send

notice of the labeling change proposed in the CBE-0 supplement, including a copy of the

information supporting the change, to the NDA holder for the RLD at the same time that the

supplement to the ANDA is submitted to FDA, unless approval of the NDA has been withdrawn.

This proposal would ensure that the NDA holder for the RLD is promptly advised of the newly

acquired information that was considered to warrant the labeling change proposed for the drug in

the CBE-0 supplement.

If approval of the NDA for the RLD has been withdrawn (for reasons other than safety or

effectiveness), FDA's evaluation of the labeling change proposed by the ANDA holder would

consider any submissions related to the proposed labeling change from any other application

holder for drug products containing the same active ingredient.

To make the safety-related changes to drug labeling described in a CBE-0 supplement

readily available to prescribing health care providers and the public while FDA is reviewing the

supplement, FDA proposes to establish a dedicated Web page (or, alternatively, to modify an

existing FDA Web page) on which FDA would promptly post information regarding the labeling

changes proposed in a CBE-0 supplement.

A supplement to an approved ANDA for a safety-related labeling change that is

submitted in a prior approval supplement or in a CBE-0 supplement would be approved upon


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approval of the same labeling change for the RLD. The proposed rule would establish a 30-day

timeframe in which all ANDA holders would be required to submit a CBE-0 supplement with

conforming labeling changes after FDA approval of a revision to the labeling for the RLD.

The proposed rule also would amend the regulations to allow submission of a CBE-0

labeling supplement for certain changes to the "Highlights of Prescribing Information" for drug

products with labeling in the PLR format. This is intended to remove an unnecessary

impediment to prompt communication of the most important safety-related labeling changes

(e.g., boxed warnings and contraindications) for drug products with labeling in the PLR format.

Finally, FDA regulations provide that FDA may take steps to withdraw approval of an

ANDA if the generic drug labeling is no longer consistent with the labeling for the RLD, subject

to certain exceptions specified in the regulations. The proposed rule would amend the

regulations to add a new exception for generic drug labeling that is temporarily inconsistent with

the labeling for the RLD due to safety-related labeling changes submitted by the ANDA holder

in a CBE-0 supplement.

Costs and Benefits

The economic benefits to the public health from adoption of the proposed rule are not

quantified. By allowing all application holders to update labeling based on newly acquired

information that meets the criteria for a CBE-0 supplement, communication of important drug

safety information to prescribing health care providers and the public could be improved. The

primary estimate of the costs of the proposed rule includes costs to ANDA and NDA holders for

submitting and reviewing CBE-0 supplements. The Agency estimates the net annual social costs

to be between $4,237 and $25,852. The present discounted value over 20 years would be in the


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range of $63,040 to $384,616 at a 3 percent discount rate, and in the range of $44,890 to

$273,879 at a 7 percent discount rate.

I. Background

A. Drug Labeling

Under the FD&C Act, the PHS Act, and FDA regulations, the Agency makes decisions

regarding the approval of marketing applications, including supplemental applications, based on

a comprehensive analysis of the product's risks and benefits under the conditions of use

prescribed, recommended, or suggested in the labeling (see 21 U.S.C. 355(d); 42 U.S.C. 262).

FDA-approved drug labeling summarizes the essential information needed for the safe

and effective use of the drug,1and reflects FDA's finding regarding the safety and effectiveness

of the drug under the labeled conditions of use. The primary purpose of labeling (commonly

referred to as the "package insert" or "prescribing information") for prescription drugs is to

provide health care practitioners with the essential scientific information needed to facilitate

prescribing decisions, thereby enhancing the safe and effective use of prescription drug products

and reducing the likelihood of medication errors. Prescription drug labeling is directed to health

care practitioners, but may include FDA-approved patient labeling (see 201.57(c)(18) (21 CFR

201.57(c)(18)) and 21 CFR 201.80(f)(2)). The over-the-counter (OTC) Drug Facts labeling is

directed to consumers and conveys information in a clear, standardized format to enable patient

self-selection of an appropriate drug and enhance the safe and effective use of the drug (see 21

CFR 201.66).

1For the purposes of this document, unless otherwise specified, references to "drugs" or "drug products" includedrugs approved under the FD&C Act and biological products licensed under the PHS Act, other than biologicalproducts that also meet the definition of a device in section 201(h) of the FD&C Act (21 U.S.C. 321(h)).


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All drugs have risks, and health care practitioners and patients must balance the risks and

benefits of a drug when making decisions about medical therapy. As a drug is used more widely

or under diverse conditions, new information regarding the risks and benefits of a drug may

become available. This may include new risks or new information about known risks.

Accordingly, all holders of NDAs, ANDAs, and BLAs are required to develop written

procedures for the surveillance, receipt, evaluation, and reporting of postmarketing adverse drug

experiences to FDA (see 314.80(b), 314.98(a), and 600.80(b) (21 CFR 314.80(b), 314.98(a),

and 600.80(b)). Application holders must promptly review all adverse drug experience

information obtained or otherwise received by the applicant from any source, foreign or

domestic, including information derived from commercial marketing experience, postmarketing

clinical investigations, postmarketing epidemiological/surveillance studies, reports in the

scientific literature, and unpublished scientific papers, and comply with applicable reporting and

recordkeeping requirements (see 314.80(b), 314.98(a), and 600.80(b)). Application holders

also must comply with requirements for other postmarketing reports under 314.81 (21 CFR

314.81) and 21 CFR 600.81 and section 505(k) of the FD&C Act (21 U.S.C. 355(k)). These

requirements include submission of an annual report (including a brief summary of significant

new information from the previous year that might affect the safety, effectiveness, or labeling of

the drug product, and a description of actions the applicant has taken or intends to take as a result

of this new information) and, if appropriate, proposed revisions to product labeling (see

314.81).

When new information becomes available that causes information in labeling to be

inaccurate, the application holder must take steps to change the content of its labeling, in

accordance with 314.70, 314.97, and 601.12 (21 CFR 314.70, 314.97, and 601.12). All


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holders of marketing applications for drug products have an ongoing obligation to ensure their

labeling is accurate and up-to-date. A drug is misbranded in violation of the FD&C Act when its

labeling is false or misleading, or does not provide adequate directions for use and adequate

warnings (see 21 U.S.C. 331(a) and (b) and 352(a), (f), and (j)).

B. Current Requirements Related to Changes to Approved Drug Labeling

For most substantive changes to product labeling, an application holder is required to

submit a prior approval supplement and receive FDA approval for the change (see 314.70(b)

and 601.12(f)(1)). However, in the interest of public health, the regulations permit certain

labeling changes based on newly acquired information about an approved drug to be

implemented upon receipt by the Agency of a supplemental application that includes the change.

These supplements are commonly referred to as "changes being effected supplements" or "CBE-

0 supplements" (see 314.70(c)(6)(iii) and 601.12(f)(2)).

The current regulations provide that application holders may submit CBE-0 supplements

for the following types of changes to product labeling:

To add or strengthen a contraindication, warning, precaution, or adverse reactionfor which the evidence of a causal association satisfies the standard for inclusion in the

labeling under 201.57(c);

To add or strengthen a statement about drug abuse, dependence, psychologicaleffect, or overdosage;

To add or strengthen an instruction about dosage and administration that is

intended to increase the safe use of the drug product;

To delete false, misleading, or unsupported indications for use or claims foreffectiveness; or


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Any labeling change normally requiring a supplement submission and approvalprior to distribution of the drug product that FDA specifically requests be submitted

under this provision.

The CBE-0 supplement procedures originated from a 1965 policy based on FDA's

enforcement discretion regarding certain labeling changes that should be placed into effect "at

the earliest possible time" (see "Supplemental New-Drug Applications," 30 FR 993, January 30,

1965). Over the years, FDA has clarified the types of labeling changes that may be made by a

CBE-0 supplement through a series of rulemakings.

In 1985, FDA updated its procedures for CBE-0 supplements and emphasized that CBE-0

supplements were intended as a narrow exception to the general rule that labeling changes

require FDA's prior approval (see "New Drug and Antibiotic Regulations"; final rule, 50 FR

7452 at 7470, February 22, 1985).

In 2006, FDA amended its regulations governing the content and format of prescription

drug labeling to require, among other things, that the labeling of new and recently approved

products include introductory prescribing information titled "Highlights of Prescribing

Information" (see 21 CFR 201.57(a); see also "Requirements on Content and Format of Labeling

for Human Prescription Drug and Biological Products"; final rule, 71 FR 3922, January 24,

2006). The "Highlights of Prescribing Information" (Highlights) is intended to summarize the

information that is most important for prescribing the drug safely and effectively, and to organize

the information into logical groups to enhance accessibility, retention, and access to the more

detailed information (see 71 FR 3922 at 3931). As part of this rulemaking, FDA amended the

CBE-0 labeling supplement provisions to exclude most changes to the information required in

the Highlights, which must be made by a prior approval supplement unless FDA specifically


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requests that the labeling change be submitted in a CBE-0 supplement or FDA grants a waiver

request under 314.90 (21 CFR 314.90).

In 2008, FDA amended the regulations governing CBE-0 supplements to codify the

Agency's view that a CBE-0 labeling supplement is appropriate only to reflect newly acquired

information and to clarify that a CBE-0 supplement may be used to add or strengthen a

contraindication, warning, precaution, or adverse reaction only if there is sufficient evidence of a

causal association with the approved product. FDA explained that these requirements are

intended to help ensure that scientifically accurate information appears in the approved labeling

for such products ("Supplemental Applications Proposing Labeling Changes for Approved

Drugs, Biologics, and Medical Devices"; final rule, 73 FR 49603 at 49604, August 22, 2008).

FDA carefully reviews any labeling change proposed in a CBE-0 supplement, as well as

the underlying information or data supporting the change. FDA has the authority to accept,

reject, or request modifications to the proposed changes as the Agency deems appropriate, and

has the authority to bring an enforcement action if the added information makes the labeling

false or misleading (see 21 U.S.C. 352(a)). If the newly acquired information changes the

benefit/risk balance for the drug, such that the product no longer meets FDA's standard for

approval, then FDA will take appropriate action (see 21 U.S.C. 355(e) and 355-1).

The CBE-0 supplement regulations allow application holders to comply with the

requirement to update labeling promptly to include a warning about a clinically significant

hazard as soon as there is reasonable evidence of a causal association with a drug

( 201.57(c)(6)), and other risk information as required by the regulations ( 201.57(c) and

201.100(d)(3)).


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C. Specific Labeling Requirements Related to Generic Drugs

The FD&C Act describes different routes for obtaining approval of two broad categories

of drug applications: An NDA containing full reports of investigations of safety and

effectiveness, for which the requirements are set out in section 505(b) and (c) of the FD&C Act,

and an ANDA, for which the requirements are set out in section 505(j).

The ANDA category can be further subdivided into an ANDA and a "petitioned ANDA."

An ANDA must contain information to show that the proposed drug product is the same as a

drug previously approved under section 505(c) of the FD&C Act (the RLD) with respect to

active ingredient(s), dosage form, route of administration, strength, labeling, and conditions of

use, among other characteristics, and is bioequivalent to the RLD. An applicant that can meet

the requirements under section 505(j) of the FD&C Act for approval may rely upon the Agency's

finding of safety and effectiveness for the RLD and need not repeat the extensive nonclinical and

clinical investigations required for approval of an NDA submitted under section 505(b)(1) of the

FD&C Act. A "petitioned ANDA" is a type of ANDA for a drug that differs from a previously

approved drug product in dosage form, route of administration, strength, or active ingredient (in

a product with more than one active ingredient), for which FDA has determined, in response to a

suitability petition submitted under section 505(j)(2)(C) of the FD&C Act, that clinical studies

are not necessary to demonstrate safety and effectiveness.

A generic drug is classified as therapeutically equivalent to the RLD if it is a

pharmaceutical equivalent and has demonstrated bioequivalence (see "Approved Drug Products

With Therapeutic Equivalence Evaluations" (the Orange Book), 33rd ed., 2013, p. vii). The

generic drug program is based on the principle that "products classified as therapeutically

equivalent can be substituted with the full expectation that the substituted product will produce


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the same clinical effect and safety profile as the prescribed product" (Orange Book, 33rd ed.,

2013, p. vii). Currently, approximately 80 percent of all drugs dispensed are generic drugs (Ref.

1). After the introduction of a generic drug, the market share of the "brand name" drug (i.e., the

drug approved in an NDA under section 505(c) of the FD&C Act) may drop substantially.

Among drugs for which a generic version is available, approximately 94 percent are dispensed as

a generic (Ref. 1). For any given brand name drug, there may be multiple approved generic

drugs, and the prescribing health care provider ordinarily would not know which generic drug

may be substituted for the prescribed product under applicable State law.

A generic drug is required to have the same labeling as the RLD at the time of approval,

except for changes required because of differences approved under a suitability petition (see

section 505(j)(2)(C) of the FD&C Act and 21 CFR 314.93) or because the drug product and the

RLD are produced or distributed by different manufacturers (see section 505(j)(2)(A)(v) of the

FD&C Act). FDA has described those differences in 314.94(a)(8)(iv) (21 CFR

314.94(a)(8)(iv)) as including, for example, differences in formulation, bioavailability, or

pharmacokinetics; labeling revisions made to comply with current FDA labeling guidelines or

other guidance; or omission of an indication or other aspect of labeling protected by patent or

exclusivity. FDA has generally taken the position that a generic drug must maintain the same

labeling as the RLD throughout the lifecycle of the generic drug product (see 314.150(b)(10)

(21 CFR 314.150(b)(10)). Thus, if an ANDA holder believes that newly acquired safety

information should be added to its product labeling, it should provide adequate supporting

information to FDA, and FDA will determine whether the labeling for the generic drug(s) and

the RLD should be revised (see 57 FR 17950 at 17961; April 28, 1992).


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Although FDA has expressed differing views on this issue over the years, FDA generally

has advised that an ANDA holder may use the CBE-0 supplement process only to update its

product labeling to conform with approved labeling for the RLD or to respond to FDA's specific

request to submit a labeling change under this provision, and may not unilaterally change ANDA

labeling in a manner that differs from the RLD (see 314.150(b)(10); see also 57 FR 17950 at

17961, and "Supplemental Applications Proposing Labeling Changes for Approved Drugs,

Biologics, and Medical Devices"; proposed rule, 73 FR 2848 at 2849; footnote 1; January 16,

2008).

At the time of FDA's adoption of the generic drug regulations in 1992, FDA believed it

was important that product labeling for the RLD and any generic drugs be the same to assure

physicians and patients that generic drugs were, indeed, equivalent to their RLD. However, as

the generic drug industry has matured and captured an increasing share of the market, tension has

grown between the requirement that a generic drug have the same labeling as its RLD, which

facilitates substitution of a generic drug for the prescribed product, and the need for an ANDA

holder to be able to independently update its labeling as part of its independent responsibility to

ensure that the labeling is accurate and up-to-date. In the current marketplace, in which

approximately 80 percent of drugs dispensed are generic and, as we have learned, brand name

drug manufacturers may discontinue marketing after generic drug entry, FDA believes it is time

to provide ANDA holders with the means to update product labeling to reflect data obtained

through postmarketing surveillance, even though this will result in temporary labeling

differences among products. In a study of FDA safety-related drug labeling changes made in

2010, FDA found that the median time from initial approval of the drug product to the time of

making the safety-related labeling change was 11 years, which confirms that data supporting


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labeling changes may become available after approval of generic versions of the drug product

(see Ref. 2). FDA found that "[t]he most critical safety-related label changes, boxed warnings

and contraindications, occurred a median 10 and 13 years after drug approval (and the range

spanned from 2 to 63 years after approval), underscoring the importance of persistent and

vigilant postmarket drug safety surveillance" (Ref. 2).

D. Recent Court Decisions

In two recent cases, the United States Supreme Court considered the issue of whether

Federal law preempts State law tort claims against pharmaceutical manufacturers for failing to

provide adequate warnings in drug product labeling ("failure-to-warn claims") (see Pliva, Inc. v.

Mensing, 131 S.Ct. 2567 (2011) and Wyeth v. Levine, 555 U.S. 555 (2009)). In Pliva v.

Mensing, the Court held that the difference between NDA and ANDA holders' ability to

independently change product labeling through CBE-0 supplements leads to different outcomes

on whether Federal labeling requirements preempt State law failure-to-warn claims. In Wyeth v.

Levine, the Court decided that Federal law does not preempt a State law failure-to-warn claim

that a brand name drug's labeling did not contain an adequate warning. The Court found that the

drug manufacturer could have unilaterally added a stronger warning to product labeling under

the CBE-0 regulation as applied to NDAs, and absent clear evidence that FDA would not have

approved such a labeling change, it was not impossible for the manufacturer to comply with both

Federal and State requirements. The Court reaffirmed that "through many amendments to the

[FD&C Act] and to FDA regulations, it has remained a central premise of federal drug regulation

that the manufacturer bears responsibility for the content of its label at all times" (555 U.S. at

570-571).


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Two years later, in Pliva v. Mensing, the Court decided that Federal law does preempt a

State law failure-to-warn claim that a generic drug's labeling did not contain an adequate

warning. The Court deferred to FDA's interpretation of its CBE-0 supplement and labeling

regulations for ANDAs, and found that Federal law did not permit a generic drug manufacturer

to use the CBE-0 supplement process to unilaterally strengthen warnings in its labeling or to

issue additional warnings through "Dear Health Care Professional" letters, which FDA

"arguesqualify as 'labeling' " (131 S.Ct. at 2576). The Court found that, under the current

regulatory scheme, it was impossible for a generic drug manufacturer to comply with its Federal

law duty to have the same labeling as the RLD and satisfy its State law duty to provide adequate

labeling (131 S.Ct. at 2578). In September 2011, Public Citizen petitioned the Agency to revise

its regulations in response to the Mensing decision (see Docket No. FDA-2011-P-0675).

As a result of the decisions in Wyeth v. Levine and Pliva v. Mensing, an individual can

bring a product liability action for failure to warn against an NDA holder, but generally not an

ANDA holder, and thus access to the courts is dependent on whether an individual is dispensed a

brand name or generic drug. The Mensing decision alters the incentives for generic drug

manufacturers to comply with current requirements to conduct robust postmarketing

surveillance, evaluation, and reporting, and to ensure that the labeling for their drugs is accurate

and up-to-date.

We are proposing to change our regulations to expressly provide that ANDA holders may

distribute revised labeling that differs from the RLD upon submission of a CBE-0 supplement to

FDA. FDA's proposed revisions to its regulations would create parity between NDA holders and

ANDA holders with respect to submission of CBE-0 supplements for safety-related labeling

changes based on newly acquired information. This proposal is also intended to ensure that


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generic drug companies actively participate with FDA in ensuring the timeliness, accuracy, and

completeness of drug safety labeling in accordance with current regulatory requirements. If this

proposed regulatory change is adopted, it may eliminate the preemption of certain failure-to-

warn claims with respect to generic drugs.

II. Description of the Proposed Rule

A. Supplement Submission for Safety-Related Labeling "Changes Being Effected" (Proposed

314.70(b)(2), (c)(6), and (c)(8) and 601.12(f)(2))

1. Equal Applicability to NDA Holders and ANDA Holders (Proposed 314.70(c)(8))

We are proposing to add 314.70(c)(8) to enable ANDA holders to submit a CBE-0

supplement for generic drug labeling that differs from the labeling of the RLD and to establish

that 314.70(c)(6)(iii) applies equally to the holder of an approved NDA or ANDA. Proposed

314.70(c)(8) states that an application holder may submit to its approved NDA or ANDA a

supplement described by 314.70(c)(6)(iii).

If an NDA holder or ANDA holder obtains or otherwise receives newly acquired

information that should be reflected in product labeling to accomplish any of the objectives

specifically described in 314.70(c)(6)(iii)(A) through (c)(6)(iii)(D), the NDA holder or ANDA

holder must submit a CBE-0 supplement (see 314.70(c)(6)(iii); see also 21 CFR 314.3(b)

(defining "newly acquired information")). As discussed in section I.A, all application holders,

including ANDA holders, are required to conduct surveillance, evaluation, and reporting of

postmarketing adverse drug experiences and, if warranted, to propose revisions to product

labeling. Proposed 314.70(c)(8) would expressly permit ANDA holders to update product

labeling promptly to reflect newly acquired information that meets the criteria described in

314.70(c)(6)(iii)(A) through (c)(6)(iii)(D) irrespective of whether the revised labeling differs


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from that of the RLD. In addition, if an ANDA holder submits a CBE-0 supplement for a

labeling change that meets the criteria described in 314.70(c)(6)(iii)(A) through (c)(6)(iii)(E),

the ANDA holder may distribute a "Dear Health Care Provider" letter (which also meets the

statutory definition of "labeling") regarding this labeling change in the same manner as an NDA

holder or BLA holder, and be subject to the same statutory prohibition against marketing a

misbranded product (see 21 U.S.C. 321(m), 331(a) and (b), and 352, and 21 CFR 201.100(d)(1)

and 202.1(l)(2)). A "Dear Health Care Provider" letter may be used to disseminate the important

new drug safety information that warranted the CBE-0 supplement, for example, a significant

hazard to health or other important change in product labeling (see 21 CFR 200.5). FDA will

continue to undertake any communication plans to health care providers (including distribution

of "Dear Health Care Provider" letters) that are part of Risk Evaluation and Mitigation Strategies

(REMS) that include one or more generic drugs (see 21 U.S.C. 355-1(i)(2)).

The obligation to ensure that labeling is accurate and up-to-date applies equally to all

ANDA holders. In certain circumstances, if the RLD approved under section 505(c) of the

FD&C Act has been withdrawn from the market, FDA may select a drug product approved in an

ANDA (including a petitioned ANDA) to be the "reference standard" that an applicant seeking

approval of an ANDA that relies upon the withdrawn RLD must use in conducting an in vivo

bioequivalence study required for approval (see 57 FR 17950 at 17954). However, the duty to

maintain accurate product labeling does not differ between an ANDA designated as the reference

standard for bioequivalence studies and other approved ANDAs.

FDA acknowledges that there may be concerns about temporary differences in safety-

related labeling for drugs that FDA has determined to be therapeutically equivalent, especially if

multiple ANDA holders submit CBE-0 supplements with labeling changes that differ from each


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other and from the RLD. FDA also recognizes that health care practitioners are unlikely to

review product labeling for each of the generic drugs that may be substituted for the prescribed

product when making treatment decisions with their patients based on the balance of potential

benefits and risks of the drug product for that patient. To address these concerns, FDA proposes

to establish a dedicated Web page (or, alternatively, to modify an existing FDA Web page) on

which FDA would promptly post information regarding the labeling changes proposed in a CBE-

0 supplement while FDA is reviewing the supplement (see proposed 314.70(c)(8) and

601.12(f)(2)(iii)). The public may subscribe to FDA's free email subscription service to receive

an email message each time there is an update to this proposed FDA Web page.

The FDA Web page would provide information about pending CBE-0 supplements for

safety-related labeling changes, including but not limited to: The active ingredient, the trade

name (if any), the application holder, the date on which the supplement was submitted, a

description of the proposed labeling change and source of the information supporting the

proposed labeling change (e.g., spontaneous adverse event reports, published literature, clinical

trial, epidemiologic study), a link to the current labeling for the drug product containing the

changes being effected, and the status of the pending CBE-0 supplement (e.g., whether FDA is

reviewing the proposed labeling change, has taken an action on the CBE-0 supplement, or has

determined that the supplement does not meet the criteria for a CBE-0 supplement). It is

expected that a valid safety concern regarding a generic drug product also would generally

warrant submission of a supplement for a change to the labeling by the NDA holder for the RLD,

as well as other ANDA holders. The CBE-0 supplements would remain posted on FDA's Web

page until FDA has completed its review and issued an action letter. If the CBE-0 supplement is

approved, the final approved labeling will be made available on the proposed FDA Web page


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through a link to FDA's online labeling repository at http://labels.fda.gov. After an adequate

time period to communicate FDA's decision regarding approval of the CBE-0 labeling

supplements and to facilitate submission of conforming CBE-0 supplements by other application

holders, as appropriate, the original entry on FDA's Web page would be archived. Approved

labeling would continue to be available at http://labels.fda.gov. As discussed in section II.B, a

prior approval supplement or CBE-0 supplement submitted by an ANDA holder will be

approved upon the approval of the same safety-related labeling change for the RLD approved in

an NDA under section 505(c) of the FD&C Act, except that if approval of the NDA for the RLD

has been withdrawn under 314.150, FDA may approve an ANDA holder's prior approval

supplement or CBE-0 supplement (see section 505(j)(2)(A)(v) of the FD&C Act and proposed

314.97(b); see also section II.A.1.b and d). Upon FDA approval of revised labeling, other

ANDA holders will be required to submit a CBE-0 supplement with conforming revisions. We

invite comment on this approach.

Proposed 314.70(c)(8) and 601.12(f)(2)(iii) state that FDA will promptly post on its

Web site information regarding labeling changes proposed in a CBE-0 supplement to an NDA,

ANDA, or BLA. This proposal is intended to enhance transparency and facilitate access by

health care providers and the public to labeling containing newly acquired information about

important drug safety issues so that such information may be used to inform treatment decisions.

We also invite comment on whether the benefits of a dedicated FDA Web page for CBE-0

supplements could be realized through modification of FDA's existing online labeling repository

(http://labels.fda.gov). For example, the online labeling repository could be modified to enable a

separate listing of pending CBE-0 supplements, thereby improving existing resources and

consolidating labeling information on a single FDA Web page.


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Current 314.70(c)(6) and 601.12(f)(2) state that the application holder may distribute

the drug accompanied by the revised labeling upon submission to FDA of a CBE-0 supplement.

However, FDA expects that if an application holder acquires important new safety-related

information that warrants submission of a CBE-0 supplement under 314.70(c)(6) or

601.12(f)(2), the application holder will use available means (e.g., distribution of revised

labeling in electronic format to the public) to distribute the revised labeling at the time of

submission of the CBE-0 supplement to FDA (compare section II.A.1.d). Indeed, the need to

promptly communicate certain safety-related labeling changes based on newly acquired

information is the basis for this exception to the general requirement for FDA approval of

revised labeling prior to distribution (see section I.B). Accordingly, we are proposing to

expressly require that applicants submit final printed labeling in structured product labeling

(SPL) format at the time of submission of the CBE-0 supplement so that the revised labeling can

be made publicly available on FDA's Web site and in other databases (e.g., DailyMed, a Web

site provided by the National Library of Medicine that includes drug labeling submitted to FDA)

promptly after submission. This proposed change would make the regulations consistent with

FDA's previous announcement that "the Agency will make the revised labeling proposed in a

CBE supplement publicly available on its Web site and through the DailyMed shortly after the

CBE supplement is received and before FDA has necessarily reviewed or approved it" (draft

guidance for industry on "Public Availability of Labeling Changes in 'Changes Being Effected'

Supplements" (2006)).2 We note that the technical means by which the CBE-0 supplements are

2When final, this guidance will represent FDA's current thinking on this topic. For the most recent version of aguidance, check the FDA Drugs guidance Web page athttp://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm.


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made publicly available through the FDA Web site may change with evolving technology and

Agency practices.

Proposed 314.70(c)(8) and 601.12(f)(2)(iii) would require the applicant to verify that

the correct information regarding the labeling changes proposed in its CBE-0 supplement

appears on FDA's Web page. If the information is incorrect, then the applicant must contact

FDA within 5 business days of posting on the FDA Web page. The applicant may determine that

information regarding the labeling changes proposed in its CBE-0 supplement has been posted

on the FDA Web page by monitoring the FDA Web page after submission of a CBE-0

supplement or subscribing to FDA's Web page to receive an email notification. FDA intends to

identify the FDA contact person(s) who should receive any corrections to such informationfor

NDAs, ANDAs, and BLAs on the proposed FDA Web page. We invite comment on whether

this is a sufficient amount of time for an applicant to check the accuracy and completeness of the

posted information regarding the CBE-0 supplement and the link to current labeling.

a. Contents of supplement. We are proposing to add 314.70(c)(8)(i) to clarify FDA's

expectations regarding the contents of a CBE-0 supplement submitted under 314.70(c)(6)(iii),

and to facilitate publication of information regarding the CBE-0 supplement on FDA's Web

page. Current 314.70(c)(4) requires that a CBE supplement include information listed in

314.70(b)(3)(i) through (b)(3)(vii), which describes information that must be included in a

CBE supplement for a manufacturing change. To clarify FDA's expectations for the contents of

a CBE-0 labeling supplement and to facilitate listing information on FDA's proposed Web page,

we are proposing to require that a CBE-0 supplement submitted under 314.70(c)(6)(iii) contain

the following information:


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i. The application number(s) of the drug product(s) involved. If a CBE-0 supplement is

being submitted by an NDA or ANDA holder to multiple applications for a drug product or

product class, the application holder should identify the application number of each application

to which the CBE-0 supplement is being submitted.

ii. A description of the labeling change proposed in the CBE-0 supplement. The

applicant should submit a proposed narrative description of the proposed labeling change in the

CBE-0 supplement for posting on the FDA Web page. This brief narrative description should

include the affected section(s) of labeling, the labeling change, and the source of the data (e.g.,

spontaneous adverse event reports, published literature, clinical trial, epidemiologic study). For

example, "Revised contraindication: Drug X is contraindicated in patients with diabetes.

Source: Published literature, epidemiologic study."

iii. The basis for the labeling change proposed in the CBE-0 supplement. The basis for

the labeling change proposed in the CBE-0 supplement should include available data supporting

the change (e.g., spontaneous adverse event reports, published literature, clinical trial,

epidemiologic study). If the supplement has been submitted in response to FDA's specific

request to submit a CBE-0 supplement for the labeling change (see 314.70(c)(6)(iii)(E)), the

applicant should describe the specific change requested by FDA and reference the FDA

communication containing the request.

iv. A copy of the product labeling proposed in the CBE-0 supplement. A copy of the

final printed labeling containing the changes being effected should be provided in SPL format for

posting on FDA's Web site and distribution to DailyMed. The application holder also should

submit a copy of the current product labeling annotated with the labeling change proposed in the

CBE-0 supplement (e.g., use of underscoring and/or strikethrough text to show the changes being


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effected in the product labeling proposed in the CBE-0 supplement as compared to the approved

labeling).

v. Confirmation that notice has been sent to the NDA holder for the RLD. If the changes

being effected supplement is submitted by an ANDA holder and approval of the NDA for the

RLD has not been withdrawn under 314.150, the ANDA holder must include in its submission

a statement confirming that the notice described in proposed 314.70(c)(8)(ii) has been sent to

the NDA holder for the RLD.

b. Notice of labeling changes being effected. We are proposing to add 314.70(c)(8)(ii)

to require an ANDA holder to send notice of the labeling change proposed in the CBE-0

supplement, including a copy of the information supporting the change (with any personally

identifiable information redacted), to the NDA holder for the RLD at the same time that the

supplement to the ANDA is submitted to FDA, unless approval of the NDA has been withdrawn

under 314.150. This proposal would ensure that the NDA holder for the RLD is promptly

advised of the newly acquired information that was considered to warrant the labeling change

proposed for the drug in the CBE-0 supplement.

The ANDA holder would be required to send a copy of the information (e.g., published

literature, spontaneous adverse event reports) supporting the labeling change described in the

CBE-0 supplement to the NDA holder for the RLD so that the NDA holder may consider this

information as part of its review and evaluation of postmarketing data under 314.80(b). If the

information supporting the ANDA holder's labeling change described in the CBE-0 supplement

contains personally identifiable information (e.g., spontaneous adverse event reports), the ANDA

holder should redact that information prior to sending a copy of the information to the NDA

holder for the RLD, in accordance with 21 CFR 20.63(f). The NDA holder has full access to the


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data upon which the RLD was approved and, in most cases, has substantial knowledge about the

postmarketing experience for the drug product. FDA's analysis of whether the labeling change

proposed by an ANDA holder in a CBE-0 supplement should be approved (and required for

inclusion in the labeling of all versions of the drug) would benefit from the views of the NDA

holder for the listed drug that was the basis for ANDA submission. Other holders of NDAs or

ANDAs for drug products containing the same active ingredient may learn of pending CBE-0

supplements by subscribing to FDA's proposed Web page, and also may submit CBE-0

supplements or provide comments to FDA regarding a pending CBE-0 supplement. This

approach to considering information from other application holders is intended to mitigate

concerns that a single ANDA holder may not possess sufficient data to perform an adequate

assessment of the potential new safety concern raised by the newly acquired information.

It should be emphasized that interpretation of postmarketing safety data is complex,

involving analysis of postapproval clinical data, detailed review of adverse drug experience

reports in the context of relevant clinical studies, estimates of drug usage and adverse drug

experience reporting rates, estimates of background rates of the adverse event, and other relevant

information. FDA recognizes that decisions about how to address a safety concern often are a

matter of judgment, about which reasonable persons with relevant expertise may disagree, and

this may be reflected in different approaches to proposed labeling changes based on newly

acquired safety information (see Guidance on "Drug Safety Information--FDA's Communication

to the Public" (2007)). Figure 1 illustrates one of the possible scenarios involving submission of

CBE-0 supplements by multiple application holders.


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Proposed 314.70(c)(8)(ii) would provide that an NDA holder or any ANDA holder may

submit (on its own initiative or in response to a request from FDA) a labeling supplement or

correspondence to its NDA or ANDA, as applicable, regarding the labeling changes proposed in

a CBE-0 supplement. It is expected that a valid safety concern regarding a generic drug product

also would generally warrant a change to the labeling through a CBE-0 supplement by the NDA

holder for the RLD and, as a consequence, other generic drug products that reference the RLD.

In the event that the NDA holder for the RLD does not submit a supplement seeking approval for

a related or conforming labeling change, FDA may send a supplement request letter to the NDA

holder or, if appropriate, notify the responsible person of new safety information under section

505(o)(4) of the FD&C Act (see 21 U.S.C. 355(o)(2)(A) defining "responsible person"). In

situations in which the safety information prompting the submission of the CBE-0 supplement

would require a label change for other drugs containing the same active ingredient, even if

approved under a different NDA, FDA also may send a supplement request letter to the persons

responsible for those other drugs.

We recognize that the authority to order safety labeling changes under section 505(o)(4)

of the FD&C Act for new safety information about a risk of a serious adverse drug experience

will not apply to all potential safety-related labeling changes (see 21 U.S.C. 355-1(b) defining

"new safety information" and "serious adverse drug experience"). Based on our experience, we

expect that NDA holders will implement safety-related labeling changes requested by FDA even

if not required under section 505(o)(4) of the FD&C Act. In circumstances in which section

505(o)(4) of the FD&C Act does not apply, if the NDA holder declined to submit a supplement

to make the change that FDA has concluded is appropriate, FDA would consider whether the


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NDA holder's failure to update its labeling would warrant the initiation of proceedings to

withdraw approval of the NDA (see section 505(e) of the FD&C Act).

It should be noted that if an NDA holder has discontinued marketing a drug product, but

approval of the NDA has not been withdrawn under 314.150, the NDA holder still must

comply with applicable statutory and regulatory requirements. These requirements include, for

example, postmarketing reporting of adverse drug experiences, submission of an annual report

(including a brief summary of significant new information from the previous year that might

affect the safety, effectiveness, or labeling of the drug product, and a description of actions the

applicant has taken or intends to take as a result of this new information) and, if appropriate,

proposed revisions to product labeling. If approval of the NDA for the RLD is withdrawn under

314.150 for reasons other than safety or effectiveness, any generic versions that remain on the

market will be expected to contain the same essential labeling.

c. Distribution of revised labeling. We are proposing to add 314.70(c)(8)(iii) and

revise 601.12(f)(2)(ii) to expressly describe our longstanding practice with respect to labeling

supplements that have been submitted as CBE-0 supplements, but that do not meet the regulatory

criteria for CBE-0 supplements, and thus do not fall within this narrow exception to the general

requirement for FDA approval of revised labeling prior to distribution. Proposed

314.70(c)(8)(iii) and 601.12(f)(2)(ii) explain that if FDA determines during its review period

that the supplement does not meet the criteria described in 314.70(c)(6)(iii) or

601.12(f)(2)(i), as applicable, the supplement will be converted to a prior approval supplement,

and the manufacturer must cease distribution of the drug product(s) accompanied by the revised

labeling. In this scenario, the manufacturer must take steps to make the drug product available

only with the previous version of the label. This may include, for example, replacing the CBE-0


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labeling with the previous labeling on the manufacturer's Web site, requesting replacement of the

CBE-0 labeling with the previous labeling on http://labels.fda.gov, and attaching the previous

package insert to the drug product as soon as feasible thereafter or at the time of next printing of

the product labeling for packaging.

This approach is consistent with our clarifying revision in proposed 314.70(c)(7), which

explains that if the Agency does not approve the supplemental application, the manufacturer

must cease distribution of the drug product(s) accompanied by the revised labeling. The current

text of 314.70(c)(7) describes the implications of a complete response letter to the applicant for

a CBE supplement for manufacturing changes, and does not expressly address CBE-0 labeling

supplements. For consistency with 314.110 (21 CFR 314.110), we are proposing to replace the

word "disapproves" in 314.70(c)(7) with the phrase "issues a complete response letter" and to

make other editorial changes for clarity.

d. Conforming labeling requirements. Proposed 314.70(c)(8)(iv) would establish a 30-

day timeframe in which ANDA holders are required to submit a CBE-0 supplement under

314.70(c)(6)(iii)(E) with conforming labeling after FDA approval of a revision to the labeling

for the RLD. Currently, FDA advises ANDA holders to revise product labeling to conform to

the labeling of the RLD "at the very earliest time possible" (see guidance for industry on

"Revising ANDA Labeling Following Revision of the RLD Labeling" (2000)). In light of the

range of timeframes in which ANDA holders currently submit such labeling supplements, we are

proposing to revise these regulations to clarify FDA's expectations regarding the timeframe for

submission of conforming labeling changes.

Proposed 314.70(c)(8)(iv) states that upon FDA approval of changes to the labeling of

the RLD, or if approval of the NDA for the RLD has been withdrawn under 314.150, upon


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FDA approval of changes to the labeling of an ANDA that relied on the RLD, any other ANDA

holder that relied upon the RLD must submit a CBE-0 supplement with conforming labeling

revisions within 30 days of FDA's posting of the approval letter for the labeling change on FDA's

Web site, unless FDA requires the ANDA holder's labeling revisions at a different time in

accordance with sections 505(o)(4) or 505-1 of the FD&C Act, or other applicable authority.

The ANDA holder would be expected to submit updated labeling for posting on

http://labels.fda.govand DailyMed at the time of submission of the CBE-0 supplement.

However, we recognize that distribution of drug products accompanied by an updated package

insert may take additional time, depending on how often the drug is packaged, the size of

manufacturer inventories, and other factors. Accordingly, proposed 314.70(c)(8)(iv) is

directed to prompt distribution of revised labeling in electronic format, and timely distribution of

drug product accompanied by an updated package insert as soon as feasible thereafter or at the

time of next printing of the product labeling for packaging.

FDA may require an ANDA holder to submit revised product labeling at a different time

for safety labeling changes required under section 505(o)(4) of the FD&C Act or for REMS

under section 505-1 of the FD&C Act. This may occur, for example, in the context of approval

of modifications to a single, shared system REMS that are made to conform to safety labeling

changes (see section 505-1(i)(1)(B) of the FD&C Act).

2. Changes to Highlights of Prescribing Information (Proposed 314.70(c)(6) and 601.12(f)(1)

and (f)(2))

We are proposing to revise 314.70(c)(6) and 601.12(f)(1) and (f)(2) to remove the

limitation on submission of CBE-0 supplements for changes to the Highlights of drug labeling in

the PLR format.


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Current 314.70(c)(6) and 601.12(f)(1) and (f)(2) exclude most changes to the

information required in the Highlights, which are classified as a "major change" that must be

made by a prior approval supplement, unless FDA specifically requests that the labeling change

be submitted in a CBE-0 supplement or FDA grants a waiver request under 314.90. This

exception reflected the Agency's earlier view that FDA review and approval of most proposed

changes to the information in the Highlights of labeling was necessary because of the difficulty

involved in summarizing the complex information presented in the full prescribing information

(see "Requirements on Content and Format of Labeling for Human Prescription Drug and

Biological Products," 71 FR 3922 at 3932, January 24, 2006).

Based on our experience implementing the PLR, we have found this restriction on CBE-0

supplements to be unnecessary in practice. In response to an applicant's inquiry about

submission of a CBE-0 supplement for a change that would affect the Highlights of drug

labeling, FDA typically waives this limitation under 314.90 or specifically requests that the

applicant proceed with a CBE-0 supplement under 314.70(c)(6)(iii)(E) or 601.12(f)(2)(i)(E).

The Highlights of drug labeling is intended to summarize the information that is most

important for prescribing the drug safely and effectively. The types of newly acquired

information that would otherwise meet the criteria for submission of a CBE-0 supplement

include the critical safety information that is presented in the Highlights. Accordingly, we

believe that limiting the availability of CBE-0 supplements for changes to the Highlights of drug

labeling in the PLR format may pose an unnecessary impediment to prompt communication of

the most important safety-related labeling changes (e.g., boxed warnings and contraindications).

Compare 50 FR 7452 at 7470, February 22, 1985 (stating that substantive changes in labeling are


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appropriately approved by FDA in advance, "unless they relate to important safety information,

like a new contraindication or warning, that should be immediately conveyed to the user").

Our proposal to remove the limitation on submission of CBE-0 supplements for changes

to the Highlights also would create parity between application holders for drugs with labeling in

the older format and application holders for drugs with PLR labeling. For example, this proposal

would eliminate differences in the ability of application holders to submit CBE-0 supplements

for a new or substantively revised contraindication based solely on whether current labeling

appeared in the older format or PLR format.

We also are proposing to make conforming revisions to 314.70(b)(2)(v)(C) to clarify

that a prior approval supplement is required for any changes to the Highlights of drug labeling

other than changes under 314.70(c)(6)(iii), except for the specified changes that may be

reported in an annual report.

3. Clarifying Revisions and Editorial Changes

We are proposing to revise the title to 314.70(c) to refer to CBE-0 supplements to

clarify the scope of paragraph (c). As revised, 314.70(c) would describe changes requiring

supplement submission at least 30 days prior to distribution of the drug product made using the

change (CBE-30 supplements) and certain changes being effected pending supplement approval

(CBE-0 supplements). We also are proposing to add titles to paragraphs (c)(1) through (c)(7) of

314.70 for clarity.

We are proposing to revise 314.70(c)(1) to clarify that submission of a CBE-0

supplement is required for any change in the labeling to reflect newly acquired information of

the type described in 314.70(c)(6)(iii). The current text of 314.70(c)(1) is directed only to


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submission of supplements for certain manufacturing changes and does not fully describe the

range of supplements for moderate changes that are described by this paragraph.

We are proposing to move the statement regarding the contents of a CBE supplement for

certain manufacturing changes from existing 314.70(c)(4) to 314.70(c)(3) without changes.

We are proposing to revise 314.70(c)(6)(iii) to clarify that an NDA holder or ANDA

holder may distribute the drug product with revised labeling upon "submission" to FDA of the

CBE-0 supplement for the labeling change, rather than upon FDA's "receipt" of the change. For

ANDAs, section 744B(a)(5) of the FD&C Act (21 U.S.C. 379j-42(a)(5)) clarifies the time when

a supplement is "submitted" to FDA, whereas the term "received" has a specific meaning that

generally refers to FDA's determination that a submitted application has met certain criteria for

completeness (see 21 CFR 314.101). This proposed revision is intended to avoid potential

confusion, and more clearly establish the date on which distribution of revised labeling may

occur.

B. Approval of Supplements to an Approved ANDA for a Labeling Change (Proposed

314.97(b))

We are proposing to revise 314.97 by designating the current text as paragraph (a) and

by adding proposed paragraph (b) to clarify the process for approval of a supplement to an

approved ANDA for a labeling change. Proposed 314.97(b) explains that a supplement to an

approved ANDA for a safety-related labeling change that is submitted in a prior approval

supplement under 314.70(b) or in a CBE-0 supplement under 314.70(c)(6) will be approved

upon approval of the same labeling change for the RLD, except that if approval of the NDA for

the RLD has been withdrawn under 314.150, FDA may approve an ANDA holder's prior

approval supplement or CBE-0 supplement.


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It has been FDA's longstanding position that an ANDA holder may submit a prior

approval supplement to request a change to product labeling, and "FDA will determine whether

the labeling for the generic and [reference] listed drugs should be revised" (57 FR 17950 at

17961, April 28, 1992; see also 57 FR 17950 at 17965 (describing requirement for "ANDA

applicants to submit a periodic report of adverse drug experiences even if the ANDA applicant

has not received any adverse drug experience reports or initiated any labeling changes")

(emphasis added)). Proposed 314.97(b) would expressly state that a prior approval supplement

to an ANDA for a safety-related change in product labeling will be approved upon approval of

the same labeling for the RLD. This approach ensures that the approved labeling for a generic

drug continues to be the same as the approved labeling of its RLD (see section 505(j)(2)(A)(v) of

the FD&C Act). If approval of the NDA for the RLD has been withdrawn under 314.150,

FDA may approve an ANDA holder's prior approval supplement for a safety-related labeling

change (see 314.105; see also proposed 314.70(c)(8)(iv)).

Similarly, FDA would approve a CBE-0 labeling supplement to an ANDA upon the

approval of the same labeling change for the RLD (see section 505(j)(2)(A)(v) of the FD&C

Act), except that if approval of the NDA for the RLD has been withdrawn under 314.150, FDA

may approve an ANDA holder's CBE-0 supplement (see 314.105; see also proposed

314.70(c)(8)(iv)). As explained in section I.B, FDA may accept, reject, or request

modifications to the labeling changes proposed in the CBE-0 supplement. FDA's evaluation of

the labeling change proposed by the ANDA holder would consider any submissions related to

the proposed labeling change from the NDA holder for the RLD and from any other NDA or

ANDA holders for drug products containing the same active ingredient. The Agency intends to

act expeditiously, taking into account the reliability of the data, the magnitude and seriousness of


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the risk, and number of CBE-0 supplements, and reach a decision on the approvability of

labeling proposed by ANDA and NDA holders regarding the safety issue at the same time. After

approval of a labeling change, other ANDA holders would be required to submit any necessary

conforming labeling changes in accordance with proposed 314.70(c)(8)(iv).

C. Exception for ANDA Labeling Differences Resulting From "Changes Being Effected"

Supplement (Proposed 314.150(b)(10)(iii))

We are proposing to revise 314.150(b)(10) to provide an additional exception regarding

circumstances in which FDA may seek to withdraw approval of an ANDA based on generic drug

labeling that is no longer consistent with the labeling for the RLD. Proposed

314.150(b)(10)(iii) would include, as a permissible difference, changes to generic drug labeling

under a CBE-0 supplement, with the understanding that such differences generally will be

temporary.

This proposed exception reflects the Agency's judgment that concerns related to

temporary differences in labeling between generic drugs and their RLDs are outweighed by the

benefit to the public health that would result from all application holders having the ability to

independently update drug product labeling to reflect newly acquired information regarding

important drug safety issues through CBE-0 labeling supplements (compare section 505(j)(10) of

the FD&C Act).

III. Legal Authority

FDA's legal authority to modify 314.70, 314.97, 314.150, and 601.12 arises from the

same authority under which FDA initially issued these regulations. The FD&C Act (21 U.S.C.

301 et seq.) and the PHS Act (42 U.S.C. 201 et seq.) provide FDA with authority over the

labeling for drugs and biological products, and authorize the Agency to enact regulations to


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facilitate FDA's review and approval of applications regarding the labeling for those products.

Section 502 of the FD&C Act (21 U.S.C. 352) provides that a drug or biological product will be

considered misbranded if, among other things, the labeling for the product is false or misleading

in any particular (21 U.S.C. 352(a); see also 42 U.S.C. 262(j)). Under section 502(f) of the

FD&C Act, a product is misbranded unless its labeling bears adequate directions for use,

including adequate warnings against, among other things, unsafe dosage or methods or duration

of administration or application. Moreover, under section 502(j) of the FD&C Act, a product is

misbranded if it is dangerous to health when used in the manner prescribed, recommended, or

suggested in its labeling.

In addition to the misbranding provisions, the premarket approval provisions of the

FD&C Act authorize FDA to require that product labeling provide adequate information to

permit safe and effective use of the product. Under section 505(c) of the FD&C Act (21 U.S.C.

355), FDA will approve an NDA only if the drug is shown to be both safe and effective for its

intended use under the conditions set forth in the drug's labeling. Under section 505(j) of the

FD&C Act, FDA will approve an ANDA only if the drug is, with limited exceptions, the same as

a drug previously approved under section 505(c) of the FD&C Act with respect to active

ingredient(s), dosage form, route of administration, strength, labeling, and conditions of use,

among other characteristics, and is bioequivalent to the RLD.

Section 351 of the PHS Act (42 U.S.C. 262) provides additional legal authority for the

Agency to regulate the labeling of biological products. Licenses for biological products are to be

issued only upon a showing that the biological product is safe, pure, and potent (42 U.S.C.

262(a)). Section 351(b) of the PHS Act prohibits any person from falsely labeling any package


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or container of a biological product. FDA's regulations in 21 CFR part 201 apply to all

prescription drug products, including biological products.

In addition, section 701(a) of the FD&C Act (21 U.S.C. 371(a)) authorizes FDA to issue

regulations for the efficient enforcement of the FD&C Act. FDA's regulations relating to CBE-0

supplements are supported by this provision. In 1965, FDA determined that, in the interest of

drug safety, manufacturers should make certain safety-related changes to their product labeling

at the earliest possible time (see 30 FR 993, January 30, 1965). Thus, for nearly 50 years, FDA,

as the Agency entrusted with administration and enforcement of the FD&C Act and the

protection and promotion of the public health, has required NDA holders, and subsequently BLA

holders, to update drug product labeling with important, newly acquired safety information

through submission of a CBE-0 supplement.

FDA's authority to extend the CBE-0 supplement process for safety-related labeling

changes to ANDA holders arises from the same authority under which our regulations relating to

NDA holders and BLA holders were issued. Nothing in the Hatch-Waxman Amendments or

subsequent amendments to the FD&C Act limits the Agency's authority to revise the CBE-0

supplement regulations to apply to ANDA holders to help ensure that generic drugs remain safe

and effective under the conditions of use prescribed, recommended, or suggested in the labeling

throughout the life cycle of the generic drug product.

In Pliva v. Mensing, the Supreme Court recognized that "Congress and the FDA retain

the authority to change the law and regulations if they so desire" (131 S. Ct. 2567, 2582).

Recently, in Mutual Pharmaceutical Co., Inc. v. Bartlett, 133 S. Ct. 2466 (2013), the Court

indicated that "Congress' decision to regulate the manufacture and sale of generic drugs in a way

that reduces their cost to patients but leaves generic drug manufacturers incapable of modifying


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either the drugs' compositions or their warnings" contributed to the outcome in that case

(preemption of the tort claim against the generic manufacturer). We do not read this language to

suggest that the Agency would not have authority to extend the CBE-0 supplement process to

ANDA holders. The changes proposed in this rulemaking are authorized under the FD&C Act,

which provides authority for FDA to permit NDA holders and BLA holders to change their

product labeling to include certain newly acquired safety-related information through submission

of a CBE-0 supplement.

IV. Analysis of Impacts

FDA has examined the impacts of the proposed rule under Executive Order 12866,

Executive Order 13563, the Regulatory Flexibility Act (5 U.S.C. 601-612), and the Unfunded

Mandates Reform Act of 1995 (Public Law 104-4). Executive Orders 12866 and 13563 direct

Agencies to assess all costs and benefits of available regulatory alternatives and, when regulation

is necessary, to select regulatory approaches that maximize net benefits (including potential

economic, environmental, public health and safety, and other advantages; distributive impacts;

and equity). The Agency believes that this proposed rule would not be an economically

significant regulatory action as defined by Executive Order 12866.

If a rule has a significant economic impact on a substantial number of small businesses,

the Regulatory Flexibility Act requires Agencies to analyze regulatory alternatives that would

minimize any significant impact of a rule on small entities. FDA has determined that this

proposed rule would not have a significant economic impact on a substantial number of small

entities.

Section 202(a) of the Unfunded Mandates Reform Act of 1995 requires that Agencies

prepare a written statement, which includes an assessment of anticipated costs and benefits,


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before proposing "any rule that includes any Federal mandate that may result in the expenditure

by State, local, and tribal governments, in the aggregate, or by the private sector, of

$100,000,000 or more (adjusted annually for inflation) in any one year." The current threshold

after adjustment for inflation is $141 million, using the most current (2012) Implicit Price

Deflator for the Gross Domestic Product. FDA does not expect this proposed rule to result in

any 1-year expenditure that would meet or exceed this amount.

The public health benefits from adoption of the proposed rule are not quantified. By

allowing all application holders to update labeling based on newly acquired information that

meets the criteria for a CBE-0 supplement, communication of important drug safety information

to prescribing health care providers and the public could be improved. The proposed rule may

reduce the time in which ANDA holders make safety-related labeling changes for generic drugs

for which approval of the NDA for the RLD has been withdrawn. In addition, the proposed rule

generally would reduce the time in which all ANDA holders make safety-related labeling

changes, by requiring such ANDA holders to submit conforming labeling changes within 30

days of FDA's posting of the approval letter for the RLD's labeling change on its Web site. The

primary estimate of the costs of the proposed rule includes costs to ANDA and NDA holders for

submitting and reviewing CBE-0 supplements. We assume that the proposed rule will have no

effect on the number of CBE-0 supplements submitted by BLA holders.

The proposed rule is expected to generate little cost. The Agency estimates the net

annual social costs to be between $4,237 and $25,852. The present discounted value over 20

years would be in the range of $63,040 to $384,616 at a 3 percent discount rate, and in the range

of $44,890 to $273,879 at a 7 percent discount rate.


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FDA has examined the economic implications of the final rule as required by the

Regulatory Flexibility Act. This proposed rule would only impose new burdens on small generic

drug manufacturers who submit CBE-0 supplements for safety-related labeling changes. Given

the small cost per submission and the uncertainty in the estimated number of CBE-0 labeling

supplements for safety-related labeling changes that may be submitted by an ANDA holder, we

do not expect this proposed rule to impose a significant impact on a substantial number of small

entities. We therefore propose to certify that that this proposed rule would not have a significant

economic impact on a substantial number of small entities.

V. Paperwork Reduction Act of 1995

This proposed rule contains collections of information that are subject to review by the

Office of Management and Budget (OMB) under the PRA (44 U.S.C. 3501-3520). A description

of these provisions is given in this document with an estimate of the annual reporting burden.

Included in the estimate is the time for reviewing instructions, searching existing data sources,

gathering and maintaining the data needed, and completing and reviewing the collection of

information.

FDA invites comments on these topics: (1) Whether the proposed collection of

information is necessary for the proper performance of FDA's functions, including whether the

information will have practical utility; (2) the accuracy of FDA's estimate of the burden of the

proposed collection of information, including the validity of the methodology and assumptions

used; (3) ways to enhance the quality, utility, and clarity of the information to be collected; and

(4) ways to minimize the burden of the collection of information on respondents, including

through the use of automated collection techniques, when appropriate, and other forms of

information technology.


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Title: Supplemental Applications Proposing Labeling Changes for Approved Drugs and

Biological Products

Description: The proposed rule would permit ANDA holders to submit a CBE-0

supplement for certain types of labeling changes based on newly acquired information. At the

time of submission, the ANDA holder would be required to send notice of the labeling change

proposed in the CBE-0 supplement, including a copy of the information supporting the change,

to the NDA holder for the RLD, unless the NDA for the RLD has been withdrawn.

Description of Respondents: Respondents to this collection of information are NDA

holders, ANDA holders, and BLA holders.

Burden Estimates: FDA regulations at 314.70 and 314.97 set forth the requirements

for submitting supplements to FDA for certain changes to an approved NDA or ANDA. These

regulations specify the submission of supplements at different times, depending on the change to

the approved application. Under 314.70(c)(6), an applicant may commence distribution of a

drug product upon receipt by FDA of a supplement for a change to the applicant's approved

application (a CBE-0 supplement). The changes for which a CBE-0 supplement may be

submitted include, among other things, changes in the labeling ( 314.70(c)(6)(iii)) to reflect

newly acquired information, for example, to add or strengthen a contraindication, warning,

precaution, or adverse reaction for which there is reasonable evidence of a causal association.

FDA currently has OMB approval (OMB control number 0910-0001) for the submission

of supplements to FDA for changes to an approved NDA or ANDA under 314.70 (including

314.70(c)(6)(iii)) and 314.97.

Under the proposed rule, ANDA holders would be permitted to submit a supplement to

FDA for certain types of labeling changes based on newly acquired information. This collection


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of information is not currently approved under OMB control number 0910-0001. Under

proposed 314.70(c)(8), if an NDA holder or ANDA holder obtains or otherwise receives newly

acquired information that should be reflected in product labeling to accomplish any of the

objectives specifically described in 314.70(c)(6)(iii), the NDA holder or ANDA holder should

submit a CBE-0 supplement to FDA. Proposed 314.70(c)(8) is intended to permit ANDA

holders to update product labeling promptly, without FDA's special permission and assistance, to

reflect newly acquired information that meets the criteria described in 314.70(c)(6)(iii)

irrespective of whether the revised labeling differs from that of the RLD.

To minimize confusion and make safety-related changes to generic drug labeling readily

available to prescribing health care providers and the public while FDA is reviewing a CBE-0

supplement, FDA would establish, under proposed 314.70(c)(8), a dedicated Web page (or,

alternatively, a modification of an existing FDA Web page) on which FDA would promptly post

information regarding the labeling changes proposed in a CBE-0 supplement. ANDA holders

would be required to verify that the correct information regarding the labeling changes proposed

in their CBE-0 supplement appears on the FDA Web page. If the information is incorrect, the

ANDA holder must contact the appropriate FDA review division within 2 business days of

posting on the FDA Web page.

At the time of submission of the CBE-0 labeling supplement to FDA, proposed

314.70(c)(8)(ii) would require the ANDA holder to send notice of the labeling change

proposed in the supplement, including a copy of the information supporting the change, to the

NDA holder for the RLD, unless the NDA for the RLD has been withdrawn.

Based on the data summarized in section IV (Analysis of Impacts), we estimate that a

total of approximately 15 ANDA holders ("number of respondents" in table 1) would submit to


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us annually a total of approximately 20 CBE-0 labeling supplements under proposed

314.70(c)(8), if this rule is finalized ("total annual responses" in table 1). We also estimate that

preparing and submitting each CBE-0 labeling supplement under proposed 314.70(c)(8) will

take approximately 12 hours per ANDA holder ("hours per response" in table 1). This burden

hour estimate includes the time needed by an ANDA holder to verify, as required under proposed

314.70(c)(8), that the correct information regarding the labeling change proposed in its CBE-0

supplement appears on the FDA Web page, and the time needed to contact FDA if the

information is incorrect.

In addition, we estimate that a total of approximately 15 ANDA holders would send

notice of the labeling change proposed in each of the 20 CBE-0 labeling supplements, including

a copy of the information supporting the change, to the NDA holder for the RLD, as required

under proposed 314.70(c)(8)(ii). We also estimate that preparing and sending each notice

would take approximately 3 hours per ANDA holder.

FDA estimates the burden of this collection of information as follows:

Table 1.--Estimated Annual Reporting Burden1

21 CFR Section No. ofRespondents

No. ofResponses per

Respondent

Total AnnualResponses

Hours perResponse

Total Hours

CBE-0 supplementsubmission by ANDAholders (314.70(c)(8))

15 1.34 20 12 240

ANDA holder notice toNDA holder(314.70(c)(8)(ii))

15 1.34 20 3 60

Total 3001There are no capital costs or operating and maintenance costs associated with this collection of information.

To ensure that comments on the information collection are received, OMB recommends

that written comments be faxed to the Office of Information and Regulatory Affairs, OMB, Attn:

FDA Desk Officer, FAX: 202-395-7245, or emailed to [email protected]. All


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comments should be identified with the title, "Supplemental Applications Proposing Labeling

Changes for Approved Drugs and Biological Products."

In compliance with the PRA (44 U.S.C. 3407(d)), the Agency has submitted the

information collection provisions of this proposed rule to OMB for review. These requirements

will not be effective until FDA obtains OMB approval. FDA will publish a notice concerning

OMB approval of these requirements in the Federal Register.

VI. Environmental Impact

The Agency has determined under 21 CFR 25.30(h) and 25.31(a) and (g) that this action

is of a type that does not individually or cumulatively have a significant effect on the human

environment. Therefore, neither an environmental assessment nor an environmental impact

statement is required.

VII. Effective Date

FDA proposes that any final rule based on this proposal become effective 30 days after

the date of its publication in the Federal Register.

We intend to apply this rule, if finalized, to any submission received by FDA on or after

the effective date. This proposed rule provides sufficient notice to all interested parties,

including NDA holders, ANDA holders, and BLA holders, to adjust their submissions and

actions by the time we issue any final rule. However, we invite comments on how a final rule

should be implemented.

VIII. Federalism

FDA has analyzed this proposed rule in accordance with the principles set forth in

Executive Order 13132. FDA has determined that the proposed rule, if finalized, would not

contain policies that would have substantial direct effects on the States, on the relationship


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